Abstract:Background and Purpose-The impact of postmenopausal estrogen replacement therapy on stroke prevention and stroke severity remains controversial. Previously we have shown that cerebral tissue infarction volume sustained after middle cerebral artery (MCA) occlusion is smaller in female than in male animals. This protection is lost after ovariectomy but is restored by 17-estradiol replacement. However, the therapeutic range for estradiol is suboptimal, since only doses resulting in a narrow range of plasma level… Show more
“…Our finding that tamoxifen has estrogen-like neuroprotective effects in the brain adds to a growing literature demonstrating estrogen-like effects of tamoxifen in the regulation of glucose transporters and IGF-1 expression in the primate cerebral cortex [25], glutamate receptor levels in the rat cerebral cortex [26, 27], and brain metabolism in humans [28]. The SERM, raloxifene and its derivatives have also been recently reported to have similar estrogen-like effects on similar end-points in the brain [26, 27, 29, 30, 31]. Collectively, these studies demonstrate that SERMs can exert estrogen-like actions in the brain in a variety of species.…”
Previous work has demonstrated that physiological concentrations of 17β-estradiol can protect the female rat brain against middle cerebral artery occlusion (MCAO)-induced ischemic damage. The present study examined whether therapeutic doses of the clinically relevant selective estrogen receptor modulator (SERM), tamoxifen, can similarly protect the female rat brain against ischemic stroke damage. Adult female rats were bilaterally ovariectomized and implanted subcutaneously with either a placebo or tamoxifen time-release pellet (0.1, 0.8 or 2.4 mg/kg/day). One week later, the animals underwent permanent MCAO to assess the protective ability of the different tamoxifen doses on brain infarct size. As expected, MCAO produced a large infarct (∼53%) of the affected cerebral hemisphere in placebo (control) animals. The 0.1 mg/kg/day dose of tamoxifen did not exhibit any significant protective effects, however; the 0.8 and 2.4 mg/kg/day doses of tamoxifen, which are in the therapeutic range, dramatically reduced infarct of the affected cerebral hemisphere (∼70% reduction) as compared to the controls. The reduction of infarct size was primarily due to protection of two major structures, the cerebral cortex and striatum. Laser Doppler analysis further revealed that tamoxifen had no significant effect on cerebral blood flow either before or after MCAO, suggesting that tamoxifen protection is independent of cerebral blood flow changes. Further studies showed that tamoxifen pellets implanted at the time of MCAO did not reduce infarct size, suggesting that pretreatment with tamoxifen is necessary to observe a protective effect. These studies suggest that clinically important SERMs may have an additional unrecognized beneficial effect of protection of the female brain.
“…Our finding that tamoxifen has estrogen-like neuroprotective effects in the brain adds to a growing literature demonstrating estrogen-like effects of tamoxifen in the regulation of glucose transporters and IGF-1 expression in the primate cerebral cortex [25], glutamate receptor levels in the rat cerebral cortex [26, 27], and brain metabolism in humans [28]. The SERM, raloxifene and its derivatives have also been recently reported to have similar estrogen-like effects on similar end-points in the brain [26, 27, 29, 30, 31]. Collectively, these studies demonstrate that SERMs can exert estrogen-like actions in the brain in a variety of species.…”
Previous work has demonstrated that physiological concentrations of 17β-estradiol can protect the female rat brain against middle cerebral artery occlusion (MCAO)-induced ischemic damage. The present study examined whether therapeutic doses of the clinically relevant selective estrogen receptor modulator (SERM), tamoxifen, can similarly protect the female rat brain against ischemic stroke damage. Adult female rats were bilaterally ovariectomized and implanted subcutaneously with either a placebo or tamoxifen time-release pellet (0.1, 0.8 or 2.4 mg/kg/day). One week later, the animals underwent permanent MCAO to assess the protective ability of the different tamoxifen doses on brain infarct size. As expected, MCAO produced a large infarct (∼53%) of the affected cerebral hemisphere in placebo (control) animals. The 0.1 mg/kg/day dose of tamoxifen did not exhibit any significant protective effects, however; the 0.8 and 2.4 mg/kg/day doses of tamoxifen, which are in the therapeutic range, dramatically reduced infarct of the affected cerebral hemisphere (∼70% reduction) as compared to the controls. The reduction of infarct size was primarily due to protection of two major structures, the cerebral cortex and striatum. Laser Doppler analysis further revealed that tamoxifen had no significant effect on cerebral blood flow either before or after MCAO, suggesting that tamoxifen protection is independent of cerebral blood flow changes. Further studies showed that tamoxifen pellets implanted at the time of MCAO did not reduce infarct size, suggesting that pretreatment with tamoxifen is necessary to observe a protective effect. These studies suggest that clinically important SERMs may have an additional unrecognized beneficial effect of protection of the female brain.
“…A number of studies have now appeared in the literature demonstrating neuroprotective actions of nonsteroidal SERMs. For instance, pretreatment with the raloxifene analogue LY353381.HCl, a raloxifene analogue, protected the caudate-putamen region of the brain of OVX female rats in an ischemia-reperfusion model of ischemic stroke [39]. LY353381.HCl did not affect cerebral blood flow, suggesting a potential direct neuroprotective effect of this SERM in the brain.…”
Estrogen is an important hormone signal that regulates multiple tissues and functions in the body. This review focuses on the neurotrophic and neuroprotective actions of estrogen in the brain, with particular emphasis on estrogen actions in the hippocampus, cerebral cortex and striatum. Sex differences in the risk, onset and severity of neurodegenerative disease such as Alzheimer's disease, Parkinson's disease and stroke are well known, and the potential role of estrogen as a neuroprotective factor is discussed in this context. The review assimilates a complex literature that spans research in humans, non-human primates and rodent animal models and attempts to contrast and compare the findings across species where possible. Current controversies regarding the WHI (Women's Health Initiative) study, its ramifications, concerns and the new studies needed to address these concerns are also addressed. Signaling mechanisms underlying estrogen-induced neuroprotection and synaptic plasticity are reviewed, including the important concepts of genomic versus nongenomic mechanisms, types of estrogen receptor involved and their subcellular targeting, and implicated downstream signaling pathways and mediators. Finally, a multicellular mode of estrogen action in the regulation of neuronal survival and neurotrophism is discussed, as are potential future directions for the field.
“…Even though no effect on lesion size was observed, raloxifene was able to significantly improve functional outcome in an in vivo traumatic brain injury model in male rats [121]. Arzoxifene (LY353381), a raloxifene analogue with better bioavailability, was able to reduce infarct volume in the striatum of ovariectomized female rats with transient MCAO [122]. However, another novel SERM, LY362321, was unable to provide protection from transient MCAO in ovariectomized female rats [123].…”
Evidence exists for the potential protective effects of circulating ovarian hormones in stroke, and oestrogen reduces brain damage in animal ischaemia models. However, a recent clinical trial indicated that HRT (hormone-replacement therapy) increased the incidence of stroke in post-menopausal women, and detrimental effects of oestrogen on stroke outcome have been identified in a meta-analysis of HRT trials and in pre-clinical research studies. Therefore oestrogen is not an agent that can be promoted as a potential stroke therapy. Many published reviews have reported the neuroprotective effects of oestrogen in stroke, but have failed to include information on the detrimental effects. This issue is addressed in the present review, along with potential mechanisms of action, and the translational capacity of pre-clinical research.
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